The invention is in the field of hematopoietic cell reconstitution.
Animals including man tend to deplete rapidly non-autologous peripheral hematopoietic cells. This is true even if the animals are immunocompromised. This phenomenon has hindered the use of allogeneic cell transfusions in immunocompromised humans. Animal model systems have been proposed to study the human hematopoietic and immunologic system. However, they are not adequately reflective of the full complement of the immune system due to the lack or decreased amount of xenogeneic peripheral hematopoietic cells.
The most frequently used animal models of the human immune system utilize severe combined immune deficiency (SCID) mice that have been injected with human peripheral blood cells or bone marrow cells; or that have been humanized by co-implantation of human fetal thymus and liver (Thy/Liv) or by implantation of human fetal bone marrow fragments. Mosier et al. (1988) Nature, 335:256; Kamel-Reid and Dick (1988) Science, 242:1706; McCune et al. (1988) Science, 241:1632; Namikawa et al. (1990) J. Exp. Med., 172:1055; Kyoizumi et al. (1992) Blood, 79:1704; Kyoizumi (1993) Blood, 81:1497; and Namikawa et al. (1993) Blood, 82:2526. Injection of human bone marrow followed by a regimen of cytokine injections has been shown to allow substantial prolongation of survival of human myeloid progenitors. Lapidot et al. (1992) Science, 255:1137. The SCID-hu Thy/Liv grafts produce phenotypically normal human T cells in the periphery for prolonged periods, allowing mechanisms of tolerance induction and T cell repertoire to be studied. Krowka et al. (1991) J. Immunol., 146:3751; Vandekerckhove et al. (1991) J. Immunol., 146:4173; Vandekerckhove et al. (1992) J. Exp. Med., 175:1033; Vandekerckhove et al. (1992) J. Exp. Med., 176:1619; and Baccala et al. (1993) J. Exp. Med., 177:1481.
SCID-hu mice are also valuable for the study of human hematopoietic stem cell development and human immunodeficiency virus (HIV) pathogenesis. Peault et al. (1991) J. Exp. Med., 174:1283; Baum et al. (1992) Proc. Natl. Acad. Sci. USA, 89:2804; McCune et al. (1990) Science, 247:564; Bonyhadi et al. (1993) Nature, 363:728; Aldrovandi et al. (1993) Nature, 363:732; and copending co-owned U.S. patent application Ser. No. 07/882,937.
The potential use of SCID-hu mice is limited, however, by the low engraftment of human cells. The current models would be greatly improved by providing a means to allow human hematopoietic cells to survive and circulate freely in the periphery of immunocompromised mice. Moreover, methods useful in increasing engraftment of human cells in SCID-hu mice have direct application in a variety of human disorders.
The mononuclear phagocyte systems of the spleen and liver are important sites of phagocytosis of both opsonized and non-opsonized particles as well as in the early phases of bacterial infection. Lockwood (1983) Clin. Hematol. 12:449. Specific elimination of macrophages in the spleen and liver can be effected by injection of liposome-encapsulated dichloromethylene diphosphonate (C12MDP). Van Rooijen et al. (1984) Cell Tissue Res., 238:355; and Van Rooijen and Claasen, In vivo Elimination of Macrophages in Spleen and Liver, Using Liposome-Encapsulated Drugs: Methods and Applications (John Wiley and Sons, Chichester, 1988). Injection of free Cl2MDP does not result in significant macrophage depletion because small, charged molecules like Cl2MDP are not subject to endocytosis by macrophages as liposomes are. Gregoriadis et al., Targeting of Drugs (Plenum Press, New York, 1982). Nor does the injection of liposome-encapsulated phosphate-buffered saline (PBS) reduce macrophage levels as neither the liposomes nor the PBS are toxic to the macrophage. However, a single intravenous injection of liposome-encapsulated Cl2MDP results in the disappearance of splenic red pulp and marginal zone macrophages with recovery of these subpopulations occurring 1-2 weeks and greater than one month respectively. Van Rooijen et al. (1989) J. Leuk. Biol., 45:97. The Cl2MDP-induced macrophage depletion can be sustained for prolonged periods (at least one month) with sequential intravenous injections. Kraal et al. (1993) Int. Arch. Allergy Immunol., 100:115.
It has now been found that the macrophages in the mononuclear phagocytic system play an important role in clearance of non-autologous hematopoietic cells and elimination of endogenous macrophages results in the ability of non-autologous hematopoietic cells to circulate and survive in the periphery of host animals.
Methods are provided for preventing depletion of peripheral non-autologous hematopoietic cells in animals including humans by substantially ablating the endogenous macrophage population. Animal models of peripheral non-autologous hematopoietic cells and the full complement of the human hematopoietic system are provided.